Psychosis occurs in 40-60% of subjects with Alzheimer disease (AD) and contributes to increased costs of caring for Veterans with AD. Current efforts to treat psychosis in AD with medications used for similar symptoms in patients without dementia have largely failed, potentially because of lack of biologic specificity. Importantly, three independent replications have found that psychosis in AD is familial, with an estimated heritability of 61%. Current genetic data support a model in which genetic variants that increase the risk for AD do so equally in AD subjects with or without psychosis. Additional variants increase the risk for psychosis, contingent on the development of AD, with the most rapid increase in onset of psychosis in early to middle stages of AD. The genetic variants for psychosis in AD overlap with those that contribute to psychosis risk in schizophrenia. Numerous studies have found that AD subjects with psychosis (AD+P) have more rapid cognitive decline, preceding psychosis onset, than AD subjects without psychosis (AD-P). Because synapse loss is the strongest correlate of cognitive decline in AD, greater synapse loss is thus likely to underlie the AD+P phenotype. The emerging picture of AD indicates that loss of dendritic spines and their synapses are driven by soluble oligomeric amyloid beta (A?) species. Soluble A?-induced spine loss depends on phosphoTau (pTau) and engages molecular mediators of synaptic plasticity, resulting in depletion of glutamate receptors (GluR, NMDAR) from the post-synaptic density (PSD). During the initial funding interval we evaluated AD-P and AD+P subjects for brain levels of kalirin protein, a RAC/Rho guanine nucleotide exchange factor with critical roles in dendritic spine maintenance and growth. These properties, and evidence of kalirin's association with psychosis risk in schizophrenia, made it a strong candidate molecule for psychosis in AD. In Braak stage 3-5 subjects, kalirin-9, and kalirin-12 were selectively reduced in AD+P. Reductions in kalirin-7 were present in both AD-P and AD+P, but markedly accelerated in AD+P. These reductions occurred despite soluble A?1-42:A?1-40 ratios that did not differ between AD+P and AD-P subjects in these stages. However, a number of critical questions remain. Kalirin-7, -9, and -12 are found in PSD fractions, however, -9 and -12 have significant expression in other compartments. Thus, determining which isoforms contribute to pathology in AD+P requires evaluating compartmental-specific expression. Although kalirin reduction is known to deplete PSD GluR1, NMDAR2B, and cause spine loss, it is not known if reduced kalirin accelerates these effects in the presence of increased soluble A?. Conversely, we and others have shown that increased expression of kalirin- 7 and -9 increases spine density. However, whether increased kalirin expression can protect against A?-induced spine loss is also unknown. We now propose to address these questions by combining human tissue studies with examination of causal relationships in animal and in vitro models: 1.To quantitate post-synaptic levels of kalirin isoforms in AD+P and AD-P; 2. To compare post-synaptic levels of glutamate receptors in AD+P and AD-P; 3. To determine if kalirin reduction enhances A?-induced spine loss. The proposed studies are highly innovative in their focus on the AD+P phenotype which is clinically important, heritable, and confers liability to a more rapidly progressive course, thus providing a novel approach to discovery of disease modifying mechanisms. Methodologic innovations include: the use of the kalirin knockout mouse developed by our consultant, Dr. Penzes; crossing the kalirin mouse with a PSAPP model of A? overproduction, and; the use of LC-SRM/MS quantification. Findings from the proposed studies will provide the basis for future studies assessing the specific pathways downstream of kalirin, and whether in vivo interventions to increase kalirin signaling may prevent or reverse A?-induced impairments in spines. Ultimately, elucidating these mechanisms may lead to cognitive and behavioral benefits for Veterans with AD+P.